Chronic administration of LIMK2 inhibitors alleviates cavernosal veno-occlusive dysfunction through suppression of cavernosal fibrosis in a rat model of erectile dysfunction after cavernosal nerve injury

Park, Juhyun; Son, Hwancheol; Chai, Ji Sun; Kim, Soo Woong; Paick, Jae Seung; Cho, Min Chul

doi:10.1371/journal.pone.0213586

Cited by 9 publications

(19 citation statements)

References 37 publications

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“…At present, the relationship between RhoA/ROCK signaling and ED has attracted the attention of many researchers. RhoA/ROCK pathway activation is closely related to erectile function, as well as cavernosal and penile fibrosis [20, 26]. The inhibition of ROCK1 or its downstream molecules, LIMK2 and Coflin, has been shown to effectively attenuate penile fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Effect of HongJing I in Treating Erectile Function and Regulating RhoA Pathway in a Rat Model of Bilateral Cavernous Nerve Injury

Zhao

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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HongJing I (HJI), a traditional Chinese herbal formula, has been confirmed to be effective for the clinical treatment of erectile dysfunction (ED). However, the mechanism of action of HJI remains unclear. Here, we aimed to investigate the effect and underlying mechanisms of HJI against ED in a rat model of bilateral cavernous nerve injury (BCNI). Rats were divided into five groups: normal control (NC), BCNI-induced ED model (M), M + low-dose HJI (HL), M + medium-dose HJI (HM), and M + high-dose HJI (HH). All groups were treated with normal saline or the relevant drug for 28 consecutive days after inducing BCNI-ED. At the end of the treatment period, the intracavernous pressure (ICP) was recorded, and histological examination was conducted using Masson’s trichrome staining. Immunofluorescence staining and western blotting were applied to detect the changes in fibrosis protein and Ras homolog A (RhoA), Rho-associated protein kinase 1 (ROCK1), and ROCK2 expression. We found that HJI effectively improved the ICP in the treatment groups. In addition, RhoA, ROCK1, and ROCK2 expression levels were increased upon BCNI-ED induction, and HJI successfully inhibited cavernosum fibrosis and the activation of RhoA/ROCK2 signaling. Overall, these results suggest that the effects of HJI in attenuating ED may be caused, at least in part, by the suppression of RhoA/ROCK2 signaling and alleviation of fibrosis. However, the precise mechanism surrounding this requires further investigation in future studies.

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Section: Discussionmentioning

confidence: 99%

Effect of HongJing I in Treating Erectile Function and Regulating RhoA Pathway in a Rat Model of Bilateral Cavernous Nerve Injury

Zhao

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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“…Следовательно, вторым важным условием полноценной эректильной функции можно считать интактность кавернозной ткани -сосудистого эндотелия и гладких миоцитов. Данное представление опирается на исследования кли нического материала и эксперименты на животных с моделированием веногенной эректильной дисфункции [25,26]. Достаточная упругость белочной оболочки является третьим фактором, необходимым для стойкой эрекции.…”

Section: Discussionunclassified

Morphological study of the valve apparatus superficial venous system of the human penis

Strelkov¹,

Астраханцев

Снегур³

2021

Androl. genit. hir.

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Introduction. Available insufficient and contradictory data on the presence, structure and possible role of the valves of the penile veins determined the aim of the study.The study objective is the examination of the valve apparatus of the deep dorsal (DDV) and superficial dorsal veins (SDV) of the human penis.Materials and methods. The material was veins obtained at the autopsy by microdissection from the coronal sulcus to the base of the penis – 51 cases – and cross sections of cavernous bodies distal to the suspensory ligament – 103 cases – a total of 154 observations. Standard histological techniques were used. Staining with hematoxilin and eosin, fuchsin and picrofuchsin, Mallory staining were used.Results. Two branches of the DDV were identified in 7.8 % of observations, usually as a division of the main trunk. DDV valves were found in 92.2 % of the observations, with the frequency of occurrence immediately distal to the suspensory ligament being about 38 %. Perhaps the valves of this localization play the role of an osteal valve. Valves were detected in 75 % of the cases in the studied area of SDV. A total of 190 valve images were obtained and analyzed. The valves have a well developed roller, collagen and smooth muscle fibers of which are woven into the middle shell of the vein wall. The base of the valve roller has fibers located in intersecting planes, which strengthens it. The flaps of the valve are thin and consist mainly of collagen fibers. Valves of DDV and SDV have a similar structure. Valves are regularly found in the envelope veins, the perforant veins of the tunica albuginea, the veins of the subshell venous plexus, the paraurethral veins. All valves have a clear orientation, aimed at unilateral outflow of blood from the penis.Conclusion. The results of the study indicate the presence of a formed valvular apparatus in the veins of the human penis, which provides unidirectional venous outflow from the cavernous bodies, preventing retrograde blood flow. The findings add to existing knowledge about the structure of the valvular apparatus of the penile veins and its potential role in erectile function and dysfunction.

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“…We conducted Masson's trichrome staining for evaluating the smooth muscle (SM)/collagen ratio (collagen content) in a routine manner, as previously described 14,24 . Also, the immunohistochemical staining for alpha‐SM actin (α‐SMA) was performed to determine smooth muscle content using a primary antibody against α‐SMA (1:100; Dako, Glostrup, Denmark), as previously described 14,24 …”

Section: Methodsmentioning

confidence: 99%

“…To evaluate HDAC signaling, Western blotting was performed in a routine manner 14,24 . The primary antibodies included anti‐TGF‐β1 (1:500, Santa Cruz Biotechnology, Dallas, USA), anti‐HDAC2 (1:2,000, Abcam, Cambridge, UK), anti‐HDAC3 (1:2,000, Cell Signaling), and anti‐collagen‐1 (1:1.000, Abcam).…”

Section: Methodsmentioning

confidence: 99%

“…The dynamic infusion cavernosometry (DIC) was performed to assess CVOF in the anesthetized rats (seven rats per each group) at 5 weeks after the surgery, as previously described 24 . Briefly, we inserted a 26‐gauge needle connected to a pressure transducer into the corpus cavernosum for assessing intracavernosal pressure (ICP), and another 26‐gauge needle was introduced into the contralateral corpus cavernosum for infusion of papaverine or saline.…”

Section: Methodsmentioning

confidence: 99%

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Rectification of cavernosal fibrosis and veno‐occlusive dysfunction by administration of suberoylanilide hydroxamic acid in a rat model of cavernosal nerve injury: Comparison with a PDE5 inhibitor

et al. 2020

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Background Cavernosal fibrosis, which is induced by cavernosal nerve (CN) injury and progresses with time, is the main cause of cavernosal veno‐occlusive dysfunction (CVOD) after radical prostatectomy. Objectives To determine whether daily oral administration of suberoylanilide hydroxamic acid (SAHA; vorinostat) for 5‐weeks from the immediate post‐injury period after CN injury would rectify CVOD by suppressing cavernosal fibrosis and normalizing HDAC pathway in a rat model of CN crush injury (CNCI) and to compare the results with those obtained using chronic administration of PDE5‐inhibitors (a positive control). Methods Fifty‐six 12‐week‐old rats were randomized into the four groups: sham surgery (S), CNCI (I), and CNCI treated with daily administration of 25.0 mg/kg SAHA (V) or 20.0 mg/kg udenafil (P). Group‐V and Group‐P received the respective treatment for 5‐weeks from the following day after CNCI. At 5 weeks after surgery, dynamic infusion cavernosometry (DIC), histological staining, and Western blot analysis were performed. Results Group‐I had a significantly decreased papaverine response, higher maintenance rate or drop rate, lower smooth muscle (SM)/collagen ratio, decreased SM content, and increased protein expression of HDAC2, HDAC3, TGF‐β1, and collagen‐1, compared with Group‐S. The three DIC parameters in Group‐V and Group‐P significantly improved compared to those in Group‐I. Except for the maintenance rate, the improvement in papaverine response and drop rate in Group‐V was not significantly different from that in Group‐P. Group‐V and Group‐P showed the rectification of SM/collagen ratio and protein expression of TGF‐β1 or collagen‐1. SM content was improved in Group‐P, but not in Group‐V. Group‐V showed the normalization of protein expression of both HDAC2 and HDAC3, whereas protein expression of only HDAC2 was partially restored in Group‐P. Discussion Treatment strategies targeting the HDAC pathway might be helpful to alleviate CVOD induced by CN injury. Conclusions According to our data, chronic administration of SAHA improves post‐injury CVOD by suppressing cavernosal fibrosis via rectifying the HDAC/TGF‐β1 pathway in nerve‐injured rats, comparable to that with PDE5 inhibitors.

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Chronic administration of LIMK2 inhibitors alleviates cavernosal veno-occlusive dysfunction through suppression of cavernosal fibrosis in a rat model of erectile dysfunction after cavernosal nerve injury

Cited by 9 publications

References 37 publications

Effect of HongJing I in Treating Erectile Function and Regulating RhoA Pathway in a Rat Model of Bilateral Cavernous Nerve Injury

Effect of HongJing I in Treating Erectile Function and Regulating RhoA Pathway in a Rat Model of Bilateral Cavernous Nerve Injury

Morphological study of the valve apparatus superficial venous system of the human penis

Rectification of cavernosal fibrosis and veno‐occlusive dysfunction by administration of suberoylanilide hydroxamic acid in a rat model of cavernosal nerve injury: Comparison with a PDE5 inhibitor

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